Citalopram is a well-known antidepressant drug that has the following structure: 
It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to US. Pat. No. 4,136,193. This patent publication describes their preparation of citalopram by one method and outlines a further method, which may be used, for preparing citalopram. The citalopram prepared was isolated in crystalline form as the oxalate, the hydrobromide and the hydrochloride salt, respectively. Furthermore, the citalopram base was obtained as an oil (B.P. 175 C/0.03 mmHg). The publication also outlines the manufacture of tablets containing salts of citalopram. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
Manufacture of crystalline citalopram base is disclosed in co-pending DK 2000 00402. This patent publication describes the preparation of crystalline citalopram base and the use of crystalline citalopram base as an intermediate in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. The publication also outlines the manufacture of tablets containing citalopram base.
Citalopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients.
It is well recognized that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
Further, active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
The problem of small particle size and poor flowability, is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active ingredient either alone or in combination with a filler and/or other conventional tablet ingredients.
One such granulation method is the “wet” granulation process. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
An alternative to the “wet” granulation method is the “melt” granulation, which is also known as the “thermal plastic” granulation process, where a low melting solid is used as the granulation agent. Initially, the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling forming a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 μm that, as many other particulate products with a small particle size, has very poor flow properties. Thus, in order to achieve appropriate dosing of the citalopram during tabletting, it was considered necessary to make a granulate of citalopram with larger particle size and improved flow properties.
The citalopram tablet that is marketed is a tablet made from granulated citalopram hydrobromide with various excipients.
In view of the fact that direct compression is much simpler and cheaper than the processes involving granulation there is a desire for a process for direct compression of citalopram hydrobromide.
The obstacles that hitherto have hindered direct compression of citalopram tablets have now been circumvented after extensive laboratory research.
It has been found that larger particles, i.e. particles of a size comparable to the size of the filler, may be prepared by a new and inventive crystallisation process and that these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such large particles.
It has also been found, that tablets with surprisingly small variation in the content of citalopram may be prepared by direct compression of citalopram hydrobromide having a significantly smaller particle size than the filler. Accurate dosing in capsules may also be achieved despite the small particle size of citalopram.